The neurotransmitter/hormone serotonin (5-hydroxytryptamine, 5-HT) regulates many physiological processes via a group of at least 14 distinct receptors that are organized into 7 subfamilies (Hoyer, D., et al., Pharmacol. Rev., 46, 1994). The 5-HT2 subfamily is composed of the 5-HT2A, 5-HT2B, and 5-HT2C receptors as determined by gene homology and pharmacological properties. There exists a substantial correlation for the relationship between 5-HT2 receptor modulation and a variety of diseases and therapies. Prior to the early 1990's the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively.
The direct or indirect agonism or antagonism of 5-HT2 receptors, either selectively or non-selectively, has been associated with the treatment of various central nervous system (CNS) disorders including obesity, depression, schizophrenia and bi-polar disorders. In the recent past the contribution of serotonergic activity to the mode of action of anti-obesity drugs has been well documented. Compounds that increase the overall basal tone of serotonin in the CNS have been successfully developed as anorectic drugs. The serotonin releasing agents, such as fenfluramine, function by increasing the amount of serotonin present in the nerve synapse. These breakthrough treatments, however, are not without side effects. Due to the mechanism of action of serotonin releasing agents, they effect the activity of a number of serotonin receptor subtypes in a wide variety of organs including those not associated with the desired mechanism of action. This non-specific modulation of the serotonin family of receptors most likely plays a significant role in the side effect profile. In addition, these compounds or their metabolites often have a high affinity for a number of the serotonin receptors as well as a multitude of other monoamine neurotransmitters and nuisance receptors. Removing some of the receptor cross reactivity would allow for the examination and possible development of potent therapeutic ligands with an improved side effect profile.
The 5-HT2C receptor is a G-protein coupled receptor. It is almost exclusively expressed in the central nervous system including the hypothalamus, hippocampus, amygdala, nucleus of the solitary tract, spinal cord, cortex, olfactory bulb, ventral tegmental area (VTA), nucleus accumbens and choroid plexus (Hoffman, B. and Mezey, E., FEBS Lett., 247, 1989). There is ample evidence to support the role of selective 5-HT2C receptor ligands in a number of disease therapies. 5-HT2C knockout mice develop a late stage obesity syndrome that is not reversed by fenfluramine or other direct acting 5-HT2C agonists such as mCPP (Nonogaki, K., et al., Nature Med., 4, 1998; Vickers, S., et. al., Psychopharmacology, 143, 1999). Administration of selective 5-HT2C agonists to rats causes a reduction in food intake and corresponding reduction in body weight (Vickers, S., et al., Br. J. Pharmacol., 130, 2000) and these responses can be blocked by administration of selective 5-HT2C antagonists (Vicker, S., et al., Neuropharmacol., 41, 2001). 5-HT2C receptor modulation in the hypothalamus can also influence thermoregulation (Mazzola-Pomietto, P, et al., Psychopharmacology, 123, 1996), sleep (Sharpley, A., et al., Neuropharmacology, 33, 1994), sexual behavior and neuroendocrine function (Rittenhouse, P. et al., J. Pharmacol. Exp. Ther., 271, 1994). Activation of 5-HT2C receptors in the VTA modulates the activity of dopaminergic neurons that are involved in aspects of depression (Di Matteo, V. et al., Trends Pharmacol. Sci., 22, 2001) and 5-HT2C receptor agonists such as WAY 161503, RO 60-0175 and RO 60-0332 are active in rodent models of depression (Cryan, J. and Lucki, I., J. Pharmacol. Exp. Ther., 295, 2000). 5-HT2C agonists have been reported to reduce the rewarding effects of nicotine administration in rats (Grottick, A., et al., Psychopharmacology, 157, 2001) and influences rodent responses to cocaine administration (Grottick, A., et al., J. Pharmacol. Exp. Ther., 295, 2000). Modulation of 5-HT2C receptors in the spinal cord can influence pain perception (Chojnacka-Wojcik, E., et al., Pol. J. Pharmacol., 46, 1994). There is also data indicating that the 5-HT2C receptor agonists mCPP and RO 60-0175 mediate penile erections in rats (Millan, M., et al., Eur J. Pharmacol. 325, 1997).
Compounds reported to bind to and activate 5-HT2C receptors are disclosed in the following documents. U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607 disclose pyridopyrrolobenz-heterocycles of formula:
where X is O, S, S(═O), or SO2; n is 0 or 1; R1 is various carbon substituents, and Z is a monosubstituent of H, methyl, or chloro.
U.S. Pat. No. 4,219,550 discloses pyridopyrrolo-benzheterocycles of formula:
where X is O or S; R1 is C1-4 alkyl or cyclopropyl; R2 is H, CH3, OCH3, Cl, Br, F, or CF3; and (A) is —CH2—, —CH(CH3)—, or —CH2CH2—.
European Patent Application EP 473,550 A1 discloses indolonaphthyridines of formula:
wherein X and Y are H or a simple ring, R1, is H, alkyl, alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl, or a mono or disubstituted carbamoylalkyl; and R3, R4, and R5 are H, halogen, alkyl, alkoxy, alkylthio or trifluoromethyl.
PCT International Patent Application WO 00/35922 discloses tetrahydro-1H-pyrazino(1,2-A-quinoxalin-5(6H)one derivatives of formula:
as being 5HT2C agonists; wherein X is CR5R6 or carbonyl; R is H or alkyl; R′ is H, alkyl, acyl, or aroyl; and R1, R2, R3, and R4 are independently, H, alkyl, alkoxy, halogen, trifluoroalkyl, cyano, alkylsulfonamide, alkyl amide, amino, alkylamino, dialkylamino, trifluoroalkoxy, acyl, or aryl.
U.S. Pat. Nos. 6,552,017, 6,548,493 PCT International Patent Application WO 00/77001, WO 00/77002, and WO 00/77010 discloses substituted heterocycle fused gamma-carbolines of formula:
wherein X is CHR, C(═O), O, S, S(═O), SO2, NR, C(═O)NR, or NRC(═O); n is 0, 1 or 2; m is 0, 1, 2 or 3; k is 1 or 2: R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, or aryl; R5 is H or alkyl, R6a and R6b are independently H, OH, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, trifluoroalkyl, alkylamino, trifluoroalkoxy, acyl, or aryl; and R7, R8, and R9 are independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, halogen, trifluoroalkyl, cyano, alkylsulfonamide, alkyl amide, amino, alkylamino, dialkylamino, trifluoroalkoxy, acyl, aryl, or heterocyclic ring.
Patent Application WO 02/59129 discloses substituted pyridoindoles of formula:
wherein X is O, S, S(═O), SO2, or NR; n is 1 or 2; k is 1 or 2: R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, or aryl; R5 and R6 are independently H, or alkyl: and R7, R8, and R9 are independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, halogen, trifluoroalkyl, cyano, alkylsulfonamide, alkyl amide, amino, alkylamino, dialkylamino, trifluoroalkoxy, acyl, aryl, or heterocyclic ring.
PTC International Patent Application WO 03/14118 discloses 1H-pyrido[4,3-b]indoles of formula:
wherein R1, R2, R3 and R4 are independently, H, halo, CF3, OCF3, CN, NO2, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, thioalkyl, C(═O)Ar, aryl, or alkyleneAr, provided that at least one of R1, R2, R3 or R4 is aryl; and R5, R6 and R7 are independently H, or various carbon substituents.
None of the above references suggest or disclose the compounds of the present invention. There remains a need to discover new compounds useful as serotonin receptor modulators, i.e. selective agonists and antagonists, which are useful in the control or prevention of central nervous system disorders. As such, the present invention discloses novel compounds which are useful as serotonin agonists and antagonists, and provide good in vitro potency.